The present invention relates to compositions suitable for oral drug delivery, and in particular to compositions in which modified amino acids and modified amino acid derivatives are used as carriers for sensitive agents such as bioactive peptides and the like. The modified amino acids or derivatives can form non-covalent mixtures with biologically-active agents which are suitable for oral administration to animals. Methods for the preparation and for the administration of such compositions are also disclosed.
Conventional means for delivering biologically-active agents, including, but not limited to, pharmaceutical and therapeutic agents, to animals are often severely limited by chemical barriers and physical barriers imposed by the body. Oral delivery of many biologically-active agents would be the route of choice if not for chemical and physico-chemical barriers such as the extreme and varying pH in the gastro-intestinal (GI) tract, exposure to powerful digestive enzymes, and the impermeability of gastro-intestinal membranes to the active agent. Among the numerous agents which are not typically suitable for oral administration are biologically-active peptides such as calcitonin and insulin. Examples of other compounds which are affected by these physico-chemical barriers are polysaccharides and particularly mucopolysaccharides, including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents are rapidly destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, or the like.
Prior methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to increase artificially the permeability of the intestinal walls; and on the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. See, for instance, U.S. Pat. No. 4,239,754; Patel et al. (1976) FEBS Letters Vol. 62, page 60; and Hashimoto et al. (1979) Endocrinol. Japan, Vol. 26, page 337. However, broad spectrum use of the aforementioned drug delivery systems is precluded for reasons including: (1) the need to use toxic amounts of adjuvants or inhibitors; (2) the lack of suitable low MW cargoes; (3) the poor stability and inadequate shelf life of the systems; (4) the difficulties in manufacturing the systems; (5) the failure of the systems to protect the active ingredient; and (6) the failure of the systems to promote absorption of the active agent.
More recently, microspheres of artificial polymers or proteinoids of mixed amino acids have been described for delivery of pharmaceuticals. For example, U.S. Pat. No. 4,925,673 describes drug containing microsphere constructs as well as methods for their preparation and use. These proteinoid microspheres are useful for delivery of a number of active agents.
There is still a need in the art for simple and inexpensive delivery systems which are easily prepared and which can deliver a broad range of biologically-active agents.
Compositions for orally delivering biologically-active agents incorporating modified amino acids, amino acid derivatives, peptides and peptide derivatives as carriers are provided. These compositions comprise
(A) at least one biologically-active agent; and
(B) at least one carrier comprising
(a)(i) at least one acylated aldehyde of an amino acid,
(ii) at least one acylated ketone of an amino acid,
(iii) at least one acylated aldehyde of a peptide,
(iv) at least one acylated ketone of a peptide, or
(v) any combination of (a)(i), (a)(ii), (a)(iii) and (a)(iv);
(b)(i) carboxymethyl-phenylalanine-leucine,
(ii) 2-carboxy-3-phenylpropionyl-leucine,
(iii) 2-benzylsuccinic acid,
(iv) an actinonin, or
(v) a compound having the formula:
Arxe2x80x94Yxe2x80x94(R1)nxe2x80x94OH 
xe2x80x83wherein: Ar is a substituted or unsubstituted phenyl or naphthyl;
Y is 
xe2x80x83or xe2x80x94SO2xe2x80x94;
R1 is 
xe2x80x83wherein:
R3 is C1 to C24 alkyl, C1 to C24 alkenyl, phenyl, naphthyl, (C1 to C10 alkyl)phenyl, (C1 to C10 alkenyl)phenyl, (C1 to C10 alkyl)naphthyl, (C1 to C10 alkenyl)naphthyl, phenyl(C1 to C10 alkyl), phenyl(C1 to C10 alkenyl), naphthyl(C1 to C10 alkyl) and naphthyl(C1 to C10 alkenyl);
R3 is optionally substituted with C1 to C4 alkyl, C1 to C4 alkenyl, C1 to C4 alkoxy, xe2x80x94OH, xe2x80x94SH, xe2x80x94CO2R5, cycloalkyl, cycloalkenyl, heterocyclic, aryl, alkaryl, heteroaryl or heteroalkaryl or any combination thereof;
R5 is hydrogen, C1 to C4 alkyl or C1 to C4 alkenyl;
R3 is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof; and
R4 is hydrogen, C1 to C4 alkyl or C1 to C4 alkenyl;
and n is from 1 to about 5;
(vi) or any combination of (b)(i), (b)(ii), (b)(iii), (b)(iv) and (b)(v); or
(c) a combination of (a) and (b).
Also contemplated is a method for preparing these compositions which comprises mixing at least one biologically active agent, with at least one carrier as described above, and optionally, a dosage vehicle.
In an alternative embodiment, these non-toxic carriers are orally administered to animals as part of a delivery system by blending or mixing the carriers with a biologically active agent prior to administration. The carriers may also form microspheres in the presence of the active agent. The microspheres containing the active agent are then orally administered. Also contemplated by the present invention are dosage unit forms that include these compositions.